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Here, we perform a genomic analysis that reveals a rapid increase in the prevalence of novel mutations in the\n                    <jats:italic>Plasmodium falciparum<\/jats:italic>\n                    chloroquine resistance transporter PfCRT following DHA\u2009+\u2009PPQ implementation. These mutations occur in parasites harboring the K13 C580Y artemisinin resistance marker. By introducing PfCRT mutations into sensitive Dd2 parasites or removing them from resistant Cambodian isolates, we show that the H97Y, F145I, M343L, or G353V mutations each confer resistance to PPQ, albeit with fitness costs for all but M343L. These mutations sensitize Dd2 parasites to chloroquine, amodiaquine, and quinine. In Dd2 parasites, multicopy\n                    <jats:italic>plasmepsin 2<\/jats:italic>\n                    , a candidate molecular marker, is not necessary for PPQ resistance. Distended digestive vacuoles were observed in\n                    <jats:italic>pfcrt<\/jats:italic>\n                    -edited Dd2 parasites but not in Cambodian isolates. Our findings provide compelling evidence that emerging mutations in PfCRT can serve as a molecular marker and mediator of PPQ resistance.\n                  <\/jats:p>","DOI":"10.1038\/s41467-018-05652-0","type":"journal-article","created":{"date-parts":[[2018,8,13]],"date-time":"2018-08-13T11:35:42Z","timestamp":1534160142000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":261,"title":["Emerging Southeast Asian PfCRT mutations confer Plasmodium falciparum resistance to the first-line antimalarial piperaquine"],"prefix":"10.1038","volume":"9","author":[{"given":"Leila S.","family":"Ross","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satish K.","family":"Dhingra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9605-0154","authenticated-orcid":false,"given":"Sachel","family":"Mok","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2923-6060","authenticated-orcid":false,"given":"Tomas","family":"Yeo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathryn J.","family":"Wicht","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9427-7139","authenticated-orcid":false,"given":"Krittikorn","family":"K\u00fcmpornsin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shannon","family":"Takala-Harrison","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benoit","family":"Witkowski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rick M.","family":"Fairhurst","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederic","family":"Ariey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Didier","family":"Menard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Fidock","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,8,17]]},"reference":[{"key":"5652_CR1","doi-asserted-by":"publisher","first-page":"17050","DOI":"10.1038\/nrdp.2017.50","volume":"3","author":"MA Phillips","year":"2017","unstructured":"Phillips, M. 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